Method for assaying radioactivity of a radionuclide

ABSTRACT

This invention relates to the generation and testing of radionuclides, and more particularly, to the generation and testing of radionuclides for use in nuclear medicine.

United States Patent Deutsch et al. [45] Apr. 18, 1972 [54] METHOD FORASSAYING RADIOACTIVITY OF A [56] References Cited RADIONUCLIDE111911121) STATES PATENTS [721 Marshall 1 i Sudbury; 1,914,935 6/1933w61fe1a1. ..250/l06 x Mead Lexmgm Nagy 2,892,086 6/1959 Carter Jr...250/106 sc ux Mass- 3,187,182 6/1965 Fratantuho.... ..250/l06 sc [73]Assignee: New England Nuclear Corporation 081 6/ 1969 Hugh s --7 /42 -6X Filed: g 1969 3,478,205 11/1969 Sporek ..250/43.5 R

[21] Appl. No.: 870,764 Primary Examiner-James W. Lawrence AssistantExaminerMorton J. F rome Related US- Application Data Attorney-Dike,Thompson & Bronstein [62] DlVlSlOll of Ser. No. 594,713, Nov. 16, 1966.ABSTRACT 0.8. C1. R, R, invention relates to the generaion and testingof l28/Ll, 128/2 R, 250/715 R. 250/ 0 T radionuclides, and moreparticularly, to the generation and [51] Int. C16 testing ofradionuclidcs for use in nuclear medicine [58] Field ofSearch50/71.5,106SC,83.3;

2 Claims, 5 Drawing Figures PATENTEDAPR 18 1912 3, 657, 541 saw 2 [IF 3FIG. 2

INVENTORS MARSHALL E. DEUTSCH LOUIS w. MEAD BY ZOLTAN NAGY ATTORNEYSPATENTEWR 18 i972 3, 657', 541

SHEET 3 BF 3 INVENTORS MARSHALL E. DEUTSCH LOUIS W. MEAD BY ZOLTAN NAGYATTORN EYS METHOD FOR ASSAYING RADIOACTIVTI'Y OF A RADIONUCLIDE This isa division of application Ser. No. 594,713 filed by us on Nov. 16, 1966.

This invention relates to the generation and testing of radionuclides,and more particularly, to the generation and testing of radionuclidesfor use in nuclear medicine.

Radionuclides, which are also known as radioisotopes, are species ofchemical elements which spontaneously emit particles and radiation. Suchradionuclides have widespread application as sources of radiation forphotographic and medical purposes. They are also used as tracers andscanners in physical and chemical systems, and in nuclear medicine. Bymonitoring the radiation emanated by radionuclides, it is possible todetermine the status of systems containing them.

In nuclear medicine, for example, radionuclides are used in scanning andin visualizing the condition of various tissues and organs. Certaintumors and malignancies have a tendency to absorb some radioactivesubstances to a greater extent than healthy tissue. Hence, the degree towhich an injected radionuclide substance becomes localized can indicateboth the presence and extent of a malignancy.

Radionuclides which are used in conjunction with physical and chemicalsystems may be obtained directly from a nuclear reactor. Radionuclidesobtained in that way often have to be transported an appreciabledistance to reach their point of use. This necessitates elaborateshielding arrangements and considerable complexity in adapting theradionuclides for local use.

Moreover, in certain situations it is desirable for the radionuclides toproduce radiation over a relatively short period of time. Otherwise, asin nuclear medicine, there could be excessive radiation exposure. Inaddition, the use of shortlived radionuclide substances permits a higherdegree of control over processes in which radiation is employed.

When short-lived radionuclides are obtained directly from a nuclearreactor, they can decay excessively before they reach their destination.

As an alternative to being obtained directly from a reactor, short-livedradionuclides can also be generated locally as selected by-products ofradioactive decay. Thus, a "daughter" radionuclide with a relativelyshort half-life can result from the spontaneous decay of a longerlivedparent. The half-life of a radionuclide represents the period of timerequired for one-half of its atoms to decay to another form of matter.When needed, the daughter radionuclide is selectively extracted from agenerating chamber containing the parent.

In the equilibrium state of the radionuclides contained in a localgenerating chamber, the apparent half-life of the daughter is the sameas that of the parent. Hence, the generating chamber provides a readilyaccessible local source of a daughter radionuclide with a relativelylong half-life, but which, upon being extracted, has a relatively shortworking life. Of course, for some situations the time relationship isdesirably reversed, and a relatively short-lived parent is used ingenerating a longer lived daughter.

Using conventional techniques for generating a daughter radionuclide ondemand, the parent is contained in the generating chamber on a suitablesubstrate. The desired daughter radionuclide is then selectivelyextracted from the chamber by a solvent that is commonly known as aneluant. During its passage through the chamber, the eluant forms aneluate" with the daughter radionuclide. This process is commonly knownas milking and the generating unit is colloquially known as a cow. It isapparent that milking is advantageous only insofar as the complexity ofthe milking process does not exceed the difficulties and limitationsencountered in the direct use of radioactive substances.

Among the disadvantages of using conventional radionuclide generators isthat a large number of separate steps is required in preparing andapplying a suitable eluant and in shielding the generating chamber.Shielding is a problem not only in the use of the generator but also inloading the chamber with the parent radionuclide. Moreover, the

fact that the local generation of a daughter radionuclide entails alarge number of distinctive steps makes it possible for contaminants toappear at various stages of the generating process.

Such contaminants pose a particularly acute problem in nuclear medicinewhere radionuclide substances that are injected into the body aredesirably sterile and free from pyrogens. The latter are heat-resistantpolysaccharides that result from bacterial activity. A satisfactorydegree of freedom from many contaminants, such as atmospheric bacteria,can usually be achieved by using conventional sterile techniques.However, with heat-resistant bacterial substances like pyrogens, theusual measures taken to insure sterile conditions often have little orno effect.

Another form of contamination that can attend the local generation of adaughter radionuclide is the undesired presence of its parent. Innuclear medicine, for example, a high degree of control is required withrespect to any radionuclide substance injected into the body, either forscanning or for radiation therapy. The undesired presence of along-lived parent radionuclide in a situation calling for ashorter-lived daughter can often produce serious and uncontrollablephysical deterioration.

Aside from contamination, the radiation hazards associated withradionuclides require that their radioactivity be measured withprecision. Direct measuring instruments of suitable precision are oftennot available at local sites. In any case, it is desirable, andsometimes necessary to adapt a sample of a locally generatedradionuclide for monitoring by commonly available instrumentation. Thisis conventionally accomplished by successive dilutions of a sample untilits radioactivity is within the range of the monitoring instrument. Notonly is this procedure time-consuming but the possibility of error isincreased to the extent that a large number of dilutions is required.

Accordingly, it is an object of the invention to facilitate the localgeneration of radionuclides. A related object is to facilitate thegeneration of radionuclides for use in nuclear medicine. Another relatedobject is to derive a relatively short-lived radionuclide daughter froma longer lived parent. Still another related object is to prevent theuse of extractive fluids of incorrect composition and amount in thelocal generation of radionuclides. A particular object is to prevent theuse of eluants of incorrect composition and strength in separating aradionuclide daughter from its parent. A further related object is tocontrol the rate of flow of an extractive fluid used in the localgeneration of radionuclide substances.

A further object of the invention is to reduce the number of stages ofhandling required for the local generation of radionuclides. A relatedobject is to provide for the local generation of radionuclides in asemi-automatic fashion.

Still a further objectof the invention is to provide a self-containedgenerator for radionuclides. A related object is to provide aradionuclide generator in which the hazard of radiation exposure isreduced. Another related object is to provide a self-contained generatorwhich is adapted to reduce the number of accessories needed to establishthe suitability of the ultimate produce of the generator.

A yet further object of the invention is to reduce the contaminationnormally incident to the generation of a desired radionuclide. A relatedobject is to facilitate the pyrogen-free generation of radionuclides foruse in nuclear medicine. Another related object is to control the levelof bacterial contamination attending the generation of a desiredradionuclide.

Still a further object of the invention is to simplify the procedure fortesting the suitability of a generated radionuclide substance. A relatedobject is to simplify the procedure for measuring radioactivity oflocally generated radionuclide substances. A further related object isto reduce the number of steps needed in measuring the radioactivity ofsuch substances. Still another related object is to facilitate theprecision measurement of highly radioactive substances with a relativelylow-range measuring instrument. Another related nun-m In,

object is to simplify the procedure for testing for the presence of anundesired radionuclide in the product of a radionuclide generator. Aparticular object is to simplify the procedure for testing for thepresence of a radionuclide parent in an eluate containing a radionuclidedaughter.

In accomplishing the foregoing and related objects, the inventionprovides a semi-closed generating system in which a chamber containingradionuclides is sealably connected to a closed, nonvented source ofextractive fluid. The fluid passes into an inlet port of the chamber asrequired to selectively extract one of the radionuclides and carry it byway of an outlet port to an outlet member. Because the source is closedand sealably connected to the chamber, the extractive fluid is largelyunaccompanied by contaminants that would otherwise be present. Where thesource is of sterile and pyrogen-free composition, the resulting systemis particularly suitable for use in nuclear medicine to generate arelatively short-lived daughter radionuclide from a longer lived parent.Since the source is closed, the extractive fluid is of predeterminedcomposition and amount. This prevents the inadvertent use of anincorrect fluid and an excessive amount of fluid.

The outlet member is adapted so that with a collector for the desiredradionuclide attached, a difference in pressure between the collectorand the source causes the extractive fluid to flow from the sourcethrough the chamber and into the collector. The difference in pressureis desirably achieved by having the collector take the form of anevacuated container and the source have a flexible sidewall. Such agenerating system is semi-automatic in that the single step of attachingthe collector brings about the elution of a desired radionuclidesubstance. In addition, with the collector attached to the outletmember, the generating system is completely closed, facilitating therealization of a radionuclide end product that is substantially freefrom contamination.

In one embodiment of the invention the outlet member includes a cannulaand the collector is an evacuated container, which is adapted tosealingly engage the cannula. The source is nonvented and has a flexiblesidewall; it contains an eluant of predetermined composition and amount.The chamber contains a parent radionuclide that is supported by asubstrate, and is connected from its inlet port to the source by aninlet conduit and from its outlet port to the outlet member by an outletconduit. When the evacuated container engages the cannula, eluant isdrawn from the source by collapse of its sidewall, due to the vacuumeffect of the evacuated container, along the inlet conduit into thechamber, where it selectively extracts a daughter radionuclide and formsan eluate that passes along the outlet conduit through the cannula tofill the container. Where the parent radionuclide is radioactivemolybdenum-99, precipitated on an alumina substrate, and the eluant is asaline solution contained in a sterile, pyrogenfree source, the daughterradionuclide in the eluate is radioactive technetium-99m which issuitable for use in nuclear medicine.

The chamber advantageously contains at least one filter and is in theform of an elongated cylinder in order to retain the substrate and topromote the uniform distribution of the eluant and avoid a breakdown bywhich the parent radionuclide could appear in the eluate during elution.Control over the rate of flow of the eluant is desirably exercised bythe use of a microporous filter between the chamber and the outletmember. The microporous filter also promotes the realization of arelatively bacteria-free eluate end product.

In accordance with one aspect of the invention, the generating system isdisposed in a container to form a self-contained generator unit. Thechamber of the generating system is shielded to attenuate radiation andis spaced from an interior wall surface of the container. The spacerthus provides an additional reduction in the level of radiation exteriorto the container. Moreover, the spacer is advantageously proportioned toreceive various accessories which are used in collecting the desiredradionuclide substance and in testing its suitability for use.

luAn

In a particular embodiment of the invention the shield for the chambertakes the form of a lead cylinder which is spaced from a cylindricalwall surface of a canister container by a foam plastic cylinder. Thelatter includes numerous wells for receiving various collectors andtesting components, and a well for a cannular outlet member of thegenerating system. To promote the passage of the eluant through thechamber, a source of extractive fluid, in the form of a plastic bag ispositioned at the bottom of the canister with the lead shield upon it.The pressure of the lead shield supplements the effect of atmosphericpressure in moving the extractive fluid through the chamber when anevacuated tube is positioned on the cannula.

In accordance with another aspect of the invention, the chamber isadvantageously of unbreakable plastic material in order to preventcrackage that could allow the leakage of radionuclide substances.Further, in addition to conduits extending from the source to thechamber and from the chamber to the outlet member, the chamber hasconduits to permit the loading of its substrate with a parentradionuclide with the chamber in position within the container of theself-contained generator unit. As a result, an operator who undertakesto load the substrate need not approach the shielded chamber by anycloser than the length of the shorter loading conduit.

In accordance with still another aspect of the invention, the extractedradionuclide substance is tested for suitability without requiringdilution and nevertheless using conventional instrumentation. For thispurpose the invention provides an assay tube which includes a capillarytube for reducing the extent of the test sample to a precisely measuredand small magnitude amount. This significantly reduces the requiredrange of the measuring instrumentation. In addition, the assay tubeincludes a stand-off portion for separating the test sample from ameasuring instrumentation by a precise distance to reduce the requiredrange still further. Accordingly, the radioactivity of even a highlyactive sample is measureable by an intermediate-range instrument. Theinvention further provides a reference radionuclide substance which isproportioned in volume and activity to establish a normalized measure ofradioactivity.

In accordance with a still further aspect of the invention, a compositetest solution is used for determining in a single step whether or notradioactive molybdenum-99 is present in the output product of a unit forgenerating radioactive technetium-99m. The composite solution is anaqueous solution of stannous chloride, hydrochloric acid and potassiumthiocyanate. This solution eliminates the need for a multiplicity oftest substances requiring multiple testing steps. When undesiredradioactive molybdenum-99 is present, the composite solution causes achange in color of a test sample of technetium-99m eluate.

Other aspects of the invention will become apparent after consideringseveral illustrative embodiments thereof, taken in conjunction with thedrawings, in which:

FIG. 1 is a perspective and cross-sectional view of a selfcontained unitfor generating radionuclide substances in accordance with the invention;

FIG. 2 is a perspective view of the the unit of FIG. 1; and

FIGS. 3A through 3C depict units for testing radionuclide slubstancesproduced by the self-contained generator of FIG.

generating assembly for Turning to FIG. 1 a self-contained unit 10 inaccordance with the invention for generating a daughter radionuclidesubstance on demand is constituted of a generating system or assembly 20disposed in a composite packaging assembly 30.

The packaging assembly 30 includes an outer container 31 and an internalspacer 32. The latter is proportioned to accommodate the generatingassembly 20, as well as various accessories 34 through 38 by which thedesired daughter radionuclide substance is collected and subsequentlytested for suitability.

The generator 10 is advantageously packaged as a hermetically sealedunit with a removable lid (not shown) for its outer container 31. In theembodiment of FIG. 1 the container 31 is a metallic canister and thespacer 32 is a multi-apertured cylinder which, for weightconsiderations, is desirably of foam plastic material such aspolystyrene or polyurethane.

Within the radionuclide generator 10, a supply of a desired daughterradionuclide is available in a chamber 21 of the generating assembly 20by virtue of the radioactive decay of a parent radionuclide. It is wellknown that many radionuclides, which also are known as radioisotopes,decay spontaneously into other radionuclides. For example, radioactivemolybdenum-99, as obtained from a nuclear reactor, spontaneously decaysinto an intermediate form of radioactive technetium (T -99m) whichbecomes technetium-99, as summarized by equation (1):

99 M 2.7 days 99 To 6 hours where M0 symbolizes radioactive molybdenumwith an atomic weight of 99 and a half-life of 2.7 days;

"'T symbolizes intermediate radioactive technetium with an atomic weightof 99 and a half-life of 6 hours; and

Tc symbolizes radioactive technetium with an atomic weight of 99 and ahalf-life of 2 X 10 years.

For the reaction symbolized in equation (1), radioactive molybdenum-99is known as the parent radionuclide and intermediate technetium-99m isthe daughter. Thus, molybdenum and intermediate technetium form aparent-daughter pair from which a relatively short-lived radionuclide isobtained from a longer lived parent. There are numerous otherparent-daughter pairs which are well known in the art for obtaining adaughter radionuclide from a parent of different halflife. Illustrativeexamples are set forth in Table I:

Since the chamber 21 of the generating assembly 20 contains radioactivematerials, it is encased by a shield 33 of material such as lead. In theembodiment of FIG. 1 the shield 33 is formed by a cylinder 33-a withplugs 33-b and 33-0 at the top and bottom. The wall of the cylindercontains upper apertures 33-11 and 33-e and lower apertures 33-f and33-g to permit access to the chamber 21. The various apertures 33-dthrough 33-g are advantageously proportioned so that their effect uponthe shielding is negligible. The upper end of the shield 33 has aplastic cap 39 to cover the ends of the upper slots 33-d and 33-e.Besides the reduction in radioactivity at the exterior of theradionuclide generator afforded by the shielding 33 an additionalreduction in exterior radioactivity results from the use of the foamplastic spacer 32. The symbol 40 on the outer surface of the container31 indicates that the unit 10 contains radioactive substances.

In order to selectively extract the desired daughter radionuclidesubstance, a suitable fluid is passed into the radionuclide chamber 21.The composition of the fluid depends upon the particular radionuclide tobe extracted. It has been theorized that in some instances, at least,the extraction takes place by the so-called elution of absorbedradionuclide particles. As a result, the terminology applicable toadsorptive processes has been applied generally to the separation of adaughter radionuclide from its parent, regardless of the actualmechanism of extraction. Hence, the extractive fluid is commonly knownas an eluant, and the solution of the eluant and the extractedradionuclide is designated as an eluate. It is also common practice torefer to the unit for producing daughter radionuclides as a cow.

The technique and mechanism in accordance with the invention foreluting, i.e. milking the desired daughter radionuclide from the chamber21 are seen more clearly with reference to FIG. 2, which shows thegenerator assembly 20 detached from the packaging assembly 30.

The generator assembly 20 includes, in addition to the chamber 21, asource 22 of eluant, an inlet conduit 23 extending from the source 22 tothe chamber 21, an outlet conduit 24, a filter unit 25, and an outletmember 26 at which the eluate containing the extracted daughterradionuclide can be col lected on demand.

Conventionally the elution of a daughter radionuclide has entailed theuse of many separate steps and components with the result that undesiredcontaminants have been able to enter at various stages of the generatingprocess. In addition, there has been the possibility of using excessivequantities of eluant and eluants of incorrect composition and strength.However, as seen from the interconnection of components in FIG. 2, thegenerating assembly 20 extends continuously in a closed fashion from thesource 22 to the outlet member 26. The closure of the generatingassembly 20 is not affected by the presence of clamped loading conduits27 and 28, whose use will be explained subsequently. Consequently, theeluate of the daughter radionuclide that is withdrawable by way of theoutlet member 26 is relatively free from contaminants that wouldotherwise be present.

Moreover, the eluant from the source 22 is of predetermined compositionand amount, preventing errors that could otherwise occur. In addition,if the materials constituting the various components of the generatingassembly 20, and particularly the source 22, are sterile andpyrogen-free, i.e. they do not contain the heat-resistant,polysaccharide by-products that characteristically accompany bacterialaction, the generating assembly 20 is suitable for producing daughterradionuclide substances for use in nuclear medicine. The presence ofpyrogens is undesirable with radionuclide substances which are injectedinto the body for scanning and other diagnostic purposes. Because oftheir resistance to heat, pyrogens are able to withstand the ordinarytemperatures that are used in sterile practice employing autoclaves.

In order to apply the extractive fluid from the source 22 to the chamber21, the invention provides a vacuum technique by which a collector inthe form of an evacuated container is used in conjunction with theoutlet member 26. For this purpose the generating assembly 20 isillustratively terminated in a cannula 26-a, while the fluid source 22is nonvented and has a collapsible sidewall. The cannula 26-a enters thebase of a cylindrical shell 26-b, which is open at its far end.

Returning momentarily to FIG. 1, the outlet member 26, including thecannula 26-a and the shell is inserted in a well of the spacer 32. Whennot being used in the elutive process, the cannula 26-a isillustratively maintained in a sterile condition by a sealing tube 35which contains an antiseptic medium such as a solution of percentalcohol. The sealing tube 35 has an attached collar 35-a that extendsabove the surface of the spacer 32 and has opposing slots to facilitategripping and removal of the sealing tube from the cannula 26-a.

A representative evacuated container for withdrawing the desireddaughter radionuclide from the generator 10 takes the form of one of theeluting tubes 34 shown in FIG. 1. Each eluting tube has a stopper 34-aand a sterilized tube cover 34-b. The stopper 34-a can be of rubber andthe tube cover 34-b, which may be omitted, can be of plastic. Forcompactness, the eluting tubes 34, of which only four are shown in FIG.1, are stored in wells of the spacer 32.

To obtain a measured supply of eluate containing the desired daughterradionuclide, the sealing tube 35 is removed from the cannula 26-a andreplaced by one of the eluting tubes 34, such as the particular tube 34shown in FIG. 2. When the eluting tube 34 has an associated tube cover34-b (not shown in FIG. 2), the latter can be retained for subsequenttesting in a fashion that will be described subsequently. Because of thevacuum in the eluting tube 34', the pressure at the source 22 is higherthan at the outlet member 26. This causes the eluant in the source 22 tobe drawn along the inlet conduit 23 into the chamber 21, where itbecomes an eluate containing the desired daughter radionuclide. Theeluate is then drawn into the outlet conduit 24, through the filter 25and to the outlet member 26, where it enters the eluating tube 34through the cannula 26-a. The vacuum in the eluting tube 34 desirablyfalls within the range from 30 percent to full vacuum.

Thus, the eluate is obtained in a semi-automatic fashion from the unit10 of FIG. 1 by merely replacing the sealing tube 35 with one of theeluting tubes 34. To limit the radioactive exposure to the withdrawneluate, the tube 34' is covered by a flexible shield (not shown). Asuitable shield in the case of a technetium-99m eluate is in the form ofa lead-loaded plastic tube that is equivalent to about one-eighth inchof lead and has a wall thickness on the order of three-eighth inch. Sucha shield reduces the radiation from the eluate drawn into the shield bya factor of about 1,000.

Turning to details of the chamber 21 in FIG. 2, it has a tubular body21-a and upper and lower end caps 21-b and 21-c which are advantageouslyof a flexible, inert and readily sealable plastic material such aspolyvinyl chloride. The inlet and outlet conduits 23 and 24 enter inletand outlet ports of the caps 2l-b and 21-c, as do loading conduits 27and 28. The use of flexible plastic for the chamber 21 reduces thepossibility that it will become fractured during use to permit theinadvertent escape of radioactive materials. The end caps 21-b and 21-cand the conduits 23, 24, 27 and 28 are sealed to the chamber 21 by asuitable plastic solvent such as cyclohexanone.

Within the tubular body 2l-a, a parent radionuclide is supported by acolumnar substrate 2l-d. In a tested embodiment of the invention forgenerating the radioactive technetium- 99m from radioactivemolybdenum-99, the support substrate 2l-r1 consisted of fine particlesof aluminum oxide ranging in size from 40 to I microns on whichradioactive molybdenum-99 had been precipitated. The substrate 2l-dshown in FIG. 2 is sandwiched between upper and lower filters 2l-e and21-f. Between the filters and the end caps are respective fiberlikemasses 21-g and 2l-h. The latter are useful in promoting thedistribution of fluid flow over the entire cross section of the columnarsubstrate 21-d; the filters also promote uniform flow and reduce thetendency of the flow to carry particles of the substrate from thechamber 21.

In a tested embodiment of the invention, the filters were porouspolyethylene discs with a pore size of approximately 70 microns and thefiber-like masses were of glass wool. In addition, the chamber 21 tookthe form of a long column which was one-half inch in internal diameterand 3 inches in internal height, giving a ratio of the column diameterto height of approximately l:6. This kind of relationship between columncross section and column height serves to promote the uniformity ofdistribution of fluid flow over the entire cross section of the column.

As shown in FIG. 2, a suitable configuration for the source 22 of eluantis a nonvented plastic bag. The bag 22 has an outlet port 22-a to whichthe inlet conduit 23 of the chamber 21 is sealably attached. Inaddition, the bag 22 has an inlet port 22 b to which a clamped inletconduit 22-c is attached. The inlet conduit 22-c is used in filling thebag 22 with an eluant of suitable composition and amount. Once the bag22 has been filled, the inlet conduit is clamped. The bag 22 isadvantageously formed from two sheets of plastic material with aperipheral sealing edge or bead 22-d. In a tested embodiment of theinvention for generating a technetium radionuclide daughter for use innuclear medicine, the bag 22 was a sterile, pyrogen-free,300-milliliter-capacity transfer pack manufactured by the FenwalLaboratories of Morton Grove, Illinois. The bag was filled withmilliliters of sterile pyrogen-free physiological saline solution. Theuse of such a bag with two collapsible sidewalls facilitates the vacuumeffect by which the eluant is drawn through the generating assembly 20.

In addition to having collapsible sidewalls, the bag 22 contains apredetermined amount of solvent, which is drawn through the chamber 21at a rate governed by the microporous filter and the extent of thevacuum in the evacuated containers 34. This, in effect, controls therate of flow through the substrate 21-d, and acts in conjunction withthe fiber-like masses to prevent a breakdown by which the parentradionuclide could be carried into solution in the eluate. Moreover, theuse of a source 22 with a pre-established supply of solvent prevents theuse of an excessive amount of solvent and also prevents an error in theuse of the correct solvent, either because of incorrect composition orconcentration.

Also shown in FIG. 2 are the details of the outlet filter unit 25, whichis for the purpose of controlling the rate of flow of the eluant drawnthrough the chamber 21 and assuring a bacteria-free eluate at the outletmember 26. In the embodiment of FIG. 2, the outlet filter unit 25 has acone-shaped base portion 25-a containing a filter pad 25-b and isthreadably connected and sealed to an internally apertured body portion25- c.' The apertured disc region of the body portion 25-c serves as asupport for the filter pad 25-b during elution. An internal gasket 25-dpromotes the seal between the base portion 25-a and the body portion25-b. Coupling the filter unit 25 to the outlet conduit 24 and to theoutlet member 26 are respective connectors 25-e and 25-f. In a testedembodiment of the invention the pad 25-b was a microporous sieve 13 mmin diameter composed of biologically inert cellulose esters and was ableto remove particles exceeding 0.22 micron in size. Since one role of thefilter unit 25 is to assure the presence of a bacteria-free eluate, thepore size of its pad 25-b desirably falls at or below 0.45 micron, whichis the reported limit on bacteria size. At the same time, the filterunit 25 controls the rate of flow of eluant through the column 21. Forvery slow rates of elution, the pore size of the pad 25!) may be assmall as 0.01 micron. Thus, a suitable range for porosity of the pad25-b is from 0.0l to 0.45 micron. Representative average rates of flowduring elution range from 4 milliliters per minute to l milliliter every5 minutes.

Considering the details of the particular interrelation between thegenerating assembly 20 and the packaging assembly 30 in FIG. 1, theinlet conduit 23 which carries the eluant from the source 22 is aplastic tube that extends along the inner wall of the spacer cylinder 32and enters the shield 33 through an upper slot 33-d. Similarly, theoutlet conduit is a plastic tube that exits from the shield 33 through aslot 33-f and extends through an aperture in the base of the spacer 32to the outlet filter 25. The nonvented plastic bag 22 which serves asthe source 22 of eluant, is positioned at the bottom of the canister 31.While the bag 22 may occupy any position in the canister, the bottomposition has the advantage of having the weight of the shield 33 bearupon it. This produces pressure which promotes the flow of the eluantthrough the generating assembly 20 when an eluting tube 34 has beenpositioned on the cannula 26-a of the outlet member 26. All of theplastic constituents of the generating assembly v20 are desirably of thesame type, such as polyvinyl chloride, but a mix of components can beused including such plastics as polyethelyene and polypropylens.

Turning to a consideration of the auxiliary conduits 27 and 28 shown inFIGS. 1 and 2, they are used in loading the chamber 21 with the parentradionuclide. In the self-contained unit 10 of FIG. 1, the loadingconduits 27 and 28 are shown with clamped ends disposed in one of theslots 33-e of the shield 33, having been sealed before the unit 10 isshipped to a destination for the local generation of a desiredradionuclide. To activate the chamber before shipment, the

conduits 27 and 28 are connected to a pumping unit (not shown). Sincethe chamber 21 is to be loaded with radioactive materials, the pumpingunit is appropriately shielded.

In the case of a technetium generator, a suitable procedure for loadingthe chamber 21 with molybdenum begins by irrigating an aluminum oxidesupport medium 2l-d with hydrochloric acid solution from the bottom ofthe column to top, i.e. into the long conduit 28 and out of the shortconduit 27. The preliminary hydrochloric acid solution irrigation may bepreceded by irrigation from bottom to top with saline solution. Suchirrigations serve to remove air bubbles and loose substrate powder fromthe chamber 21. In addition, the preliminary pass with hydrochloric acidreadies the substrate 21-d for precipitation of the parent molybdenum-99radionuclide, which is then passed in solution through the column fromtop to bottom.

One form of molybdenum solution for passage through the column isobtained by irradiating nonradioactive molybdenum oxide with thermalneutrons to produce molybdenum-99 oxide, which is dissolved in ammoniumhydroxide and adjusted to a hydrogen-ion concentration of between 3 and3.5.

Once the substrate has been wetted by the molybdenum solution,precipitation of the molybdenum upon the substrate is carried out by theflow, from top to bottom, of a suitable medium such as a 0.1 normalhydrochloric acid solution. A final irrigation of the alumina column2l-d takes place with saline solution from top to bottom to ready thechamber 21 for use. The final irrigation rinses out the acid, as well asany molybdenum that has been precipitated and additional fine particlesof alumina.

As an alternative to loading the chamber 21 with molybdenum using theauxiliary conduits 27 and 28, the latter conduits may be omittedcompletely and loading can be accomplished using the inlet and outletconduits 23 and 24 before their respective attachments to the source 22and the filter unit 25.

It will be apparent that where the column is to support a differentparent radionuclide, the substrate 21-d and various fluids and rinsesare selected accordingly. For example, substrates of zirconia and silicamay be employed. It will also be apparent that with some parentradionuclides the support medium takes other forms, including ionexchange resins.

Because of the auxiliary conduits 27 and 28 the column 21 does not haveto be handled directly during loading and the operator does not need toapproach the column closer than the length of the upper conduit 27. Inaddition, the lead shield 33 and the spacer 32 provide substantialradiation protection during loading. In a tested embodiment of theinvention, using a canister 6 inches in diameter with molybdenum-99 inthe generating chamber the respective wall thicknesses of thecylindrical shield 33 and the spacer 32 were three-fourths and 2 inches.The shield 33 reduced the radiation external to the canister from thechamber by a factor of the separation between the shield and thecanister provided by the spacer 32 gave an additional reduction inexternal radiation by a factor of 2.

Where the generator is to be used in nuclear medicine, it is importantto keep the bacteria count to a low level. One sterile technique forloading the chamber with substrate, before it is activated, is to fillthe chamber with alumina with the upper plug 21-b removed, insert andseal the upper plug, sterilize the chamber, insert it into the well ofthe spacer 32 in FIG. 1 and activate it with molybdenum solution whichhas been passed through a microporous filter in the manner described.

The insertion of the eluting tube 34' on the cannula 26-a of FIG. 2 ismerely the first step in obtaining a desired daughter radionuclidesubstance. It is also necessary to measure the radioactivity of theextracted substance, as well as check for the undesired presence of theparent, which may have been carried inadvertently from the chamber 21.

The radioactivity of the extracted substance will determine the extentof its use. This is desirably measured with precision, particularlywhere the radionuclide substance is to be injected into the body for usein nuclear medicine. To determine the extent of the radioactivity of theeluate, the composite unit 10 of FIG. 1 includes, for each eluting tube34, a companion assay tube 36. Each assay tube 36 is convenientlydisposed in an adjoining well near the eluting tube 34 with which it isused.

A representative assay tube 36 is shown in FIG. 3A, as withdrawn from anassay well in the spacer 32 of FIG. 1. The assay tube 36' has a bodysection 36-a with one end proportioned to receive a compartment 36-b.The other end of the body section 36-a is open and proportioned to beinserted into a measuring instrument. When positioned in an assay wellof the unit 10 in FIG. 1, the assay tube 36' has its open end at thebase of the well and its compartment 36-b protrudes above the spacer 32to facilitate removal. Within the compartment 36-b is a small capillarytube 36-c. It will be apparent that the capillary tube may alternativelybe stored in the body section 36-c, in which case a cap (not shown) maybe placed at the open end of the assay tube 36.

The radioactivity of the daughter radionuclide substance extracted fromthe chamber 21 can be appreciable. Consequently, it is desirable toscale the measured radioactivity downwardly so that conventionallyavailable instrumentation, such as a scintillation counting system, canbe employed.

Ordinarily in using a scintillation counting system, a radioactivesample is diluted to reduce its radioactivity. This presents problems inobtaining precisely measured dilutions and increases the radiationhazard during measurement. However, using the assay tube 36 of FIG. 3A,the activity of the extracted substance is measured without diluting thesample while using the low-level counting system.

The capillary tube 360 is used to obtain a precisely measured sample ofsmall extent, thus significantly reducing the level of radioactivity ofthe measured substance. The barrel of the body section 36-a of the assaytube 36 constitutes a standoff distance d for the measuringinstrumentation permitting a further reduction in the monitoredradioactivity.

In a tested model of the invention for assaying technetium- 99m, thecapillary tube 36-b had a capacity of l lambda, i.e. l microliter orone-thousandth of a milliliter. This gave a reduction by a factor of1,000 to the radioactivity associated with a conventional l-millilitersample. In addition, the stand-off distance d of the barrel of the mainsection 35-a was 3 inches, producing a further reduction inradioactivity by a factor of 35 A step in the testing procedure isillustrated by FIG. 3B. The plastic cover 34-b, that was retained whenthe tube 34' of FIG. 2 was removed from its well in the spacer 32 ofFIG. 1, has a concave outer surface. The eluting tube 34', with itsflexible shield in place (not shown), is withdrawn from the cannula 26-bof FIG. 2, and the sealing tube 35 is replaced on the cannula as shownin FIG. 1. The eluting tube 34 is inverted several times after removalfrom the cannula 26-a. This has the effect of thoroughly mixing itscontents. Using a sterile technique, a portion 41 of the eluate, forexample one-tenth milliliter, is withdrawn by a syringe (not shown) andejected into the cap cover 34'-b of FIG. 3A.

The capillary tube 360 is then removed from the compartment 36-b of theassay tube 36' and held at an angle to the vertical by forceps 42 orsome other suitable holder, in the eluate 41 in the cap cover 34'-b.When the capillary tube is full, it contains a reduced, but preciseamount of the eluate, for example, 1 microliter. The capillary tube 360is then returned to the compartment 36-b, which is in turn replaced onthe body section 36-a. The open end of the assay tube 36' is thenpositioned with respect to monitoring instrumentation, such as the wellscintillation arrangement 50 of FIG. 3C. Such a system includes aso-called well scintillation counter 51, which is a leadshielded chamberin which are produced electrical impulses in accordance with theradioactivity of the sample in its well 52. In one form of counter 51, acrystal which responds to radiation by emitting light is opticallyconnected to a photoelectric cell which converts the emitted light intoelectrical impulses. The impulses produced in the chamber 51 areconveyed to a scaler 53 by a connecting cable 54. The scaler is astandard electronic instrument which periodically records one impulseout of a specified number of nuclear disintegrations in the chamber 51.Thus, the indicating instrument 53 scales the activity monitored by theassociated chamber 51.

In using the assay tube 36' with the scintillation arrangement 50 ofFIG. 3C, the uncapped end of the tube 36 is inserted into the well 52 sothat the compartment 36-b containing the eluate-filled capillary tube36-0 is away from the well 52 by the stand-off distance d. In addition,the capillary tube 36-c occupies a reproducible position within thechamber 36- b, such as the slanting position shown in FIG. 3C. Thelatter position is assumed by lightly tapping the side of the chamber36-); before the scaler is read. The relative scale of the tube 36 withrespect to the counter well 52 has been greatly exaggerated for the sakeof clarification. In the case of assaying technetium-99m, the scaler 53is set in conventional fashion with its base line between 50 and 100 kevsince technetium- 99m has an energy of I40 kev.

To calibrate the reading of the scaler 53, the invention provides areference assay tube 37, shown positioned in a well of the spacer 32 ofFIG. 1. The reference assay tube 37 is similar in configuration to theassay tubes 35, except that its capillary tube (not shown) is filledwith a cobalt-57 standard with a radioactivity that corresponds at themonitoring instrument 50, to an activity, within 5 percent, of 1.0millicurie per milliliter of technetium-99m. The required amount ofcobalt-57 is that which produces the same instrument indication as asample of technetium-99m with a known activity of 1.0 millicurie permilliliter. The reference assay tube 37 may be color-coded todistinguish it from the assay tubes 35. Consequently, the activity ofthe generated eluate is directly established, without having to usescale and sensitivity factors, by dividing the count indicated by thescaler 53 for a prescribed interval of time by the corresponding countfor the reference tube 37. The associated formula for establishing theactivity A of the eluate in millicuries per milliliter is given byequation (2):

A=(N /N )i 2 where N is the indicated count for the eluate for aprescribed interval of time, and

N is the indicated count for the standard for the same interval of time.In the case of radioactive technetium-99m, a representative assay is 2.0millicuries per milliliter, and a typical injection for scanningpurposes in nuclear medicine is between 2.0 and 10.0 millicuries. Thus,if a lO-millicurie injection is desired and the assay is 2.0 millicuriesper milliliter, 5 milliliters are injected.

It will be apparent that a wide variety of alternative instrumentationmay also be employed in measuring the radioactivity of an eluategenerated in accordance with the invention, while employing theassaytube 36. For example, the assay tube 36, with an eluate-loadedcapillary tube in its compartment 36-b, may be positioned with respectto a radioisotope scanner of the kind used in nuclear medicine, and thescanner may be used to obtain an estimate of its content ofradioactivity. In addition, the sample used to fill the capillary tubemay be placed in one of the cavities of a multicavity tray instead ofthe plastic cap 34'-b of FIG. 3B.

In any case, the eluate is desirably tested for break-through of itsparent radionuclide before being injected. Where technetium-99m is thedaughter radionuclide and is to be injected into the body, such a testis mandatory since the parent molybdenum-99 may be toxic in excessiveamounts.

The invention provides for testing for a break-through of molybdenumusing a single test solution, in place of the multiplicity of separatetesting solutions usually required. This is accomplished using a droppervial 38, which is also positioned in one of the wells of the spacer 32of FIG. 1. Several droplets of test solution are applied to the eluatein the cover 34-b of FIG. 3 from the vial 38. A change in color to pinkindicates the undesired presence of the parent radionuclide.Alternatively, when a multicavity tray is employed for the test sample,the

cavity is filled to a first predetermined level to provide a sample forassay purposes and is then filled to a second level to test for thepresence of molybdenum-99.

The composite test solution for molybdenum-99 is an aqueous solution ofstannous chloride, potassium thiocyanate, and hydrochloric acid.Representative proportions for approximately a 100-milliliter amount ofthe composite solution are within the ranges shown by Table II:

TABLE II Ingredient Amount Stannous chloride (SnCI l-lO grams One molarhydrochloric acid solution LOM HCl) 5-20 milliliters Potassiumthiocyanate (KSCN) 5-25 grams Water (H O) to complete a volume of 100milliliters In a particular solution for testing for the undesiredpresence of molybdenum-99 in an eluate of technetium-99m, ingredientswere 10 grams of stannous chloride, 5 milliliters of molar hydrochloricacid solution, 5 grams of potassium thiocyanate and 100 milliliters ofwater. It has been determined experimentally that the limit of detectionusing the foregoing test solution is approximately 1.0 microgram ofmolybdenum- 99 per milliliter of technetium-99m.

Other adaptations and modifications of the invention will occur to thoseskilled in the art.

We claim: 1. The method of assaying the radioactivity of a radionuclidein a liquid which comprises the steps of I. loading a capillary tubewith a precise and predetermined quantity of said liquid and 2.positioning the capillary tube thus loaded at a prescribed distance ofseparation with respect to a radioactivity counting medium in aradioactivity measurement instrument, which is sensitive to theradiation emanating from said radionuclide and which has a well, saidstep of loading said capillary tube including a. dipping the end of saidcapillary tube into a sample of said liquid thereby to load saidcapillary tube with a precise and reproducible predetermined reducedquantity of said liquid, the step of positioning said capillary tubeincluding:

b. placing said capillary tube loaded with said liquid in a compartmentsection of an assay tube, said compartment section with said loadedcapillary tube contained therein being secured to one end of a spacersection of said assay tube with said loaded capillary tube supportedtherein on a supporting surface,

0. inserting said opposite end of said spacer section into said well ofsaid measurement instrument until said spacer section engages acooperating surface of said measurement instrument to limit the movementof the assay tube in the well to a reproducible position in which saidcapillary tube is reproducibly spaced said prescribed distance from saidcounting medium,

01. taking a measure of the radioactivity of said liquid in saidcapillary tube by said counting medium while said assay tube is held insaid position in said well, said spacer section being proportioned tohold said loaded capillary tube at said prescribed distance from saidcounting medium, whereby the indication of said instrument is a measureof the radioactivity of said liquid.

2. The method as defined in claim 1 further including the step ofobtaining a calibration measure of said instrument using a calibrationsample of a reference radionuclide substance in a capillary tubepositioned at said prescribed distance of separation with respect tosaid counting medium, said calibration sample being proportioned involume and activity to provide a normalized measure of radioactivity,whereby the radioactivity of said liquid is determinable directly by theratio of the indication of said instrument for said liquid with theindication of said instrument for said reference substance.

inn/van

1. The method of assaying the radioactivity of a radionuclide in aliquid which comprises the steps of
 1. loading a capillary tube with aprecise and predetermined quantity of said liquid and
 2. positioning thecapillary tube thus loaded at a prescribed distance of separation withrespect to a radioactivity counting medium in a radioactivitymeasurement instrument, which is sensitive to the radiation emanatingfrom said radionuclide and which has a well, said step of loading saidcapillary tube including a. dipping the end of said capillary tube intoa sample of said liquid thereby to load said capillary tube with aprecise and reproducible predetermined reduced quantity of said liquid,the step of positioning said capillary tube including: b. placing saidcapillary tube loaded with said liquid in a compartment section of anassay tube, said compartment section with said loaded capillary tubecontained therein being secured to one end of a spacer section of saidassay tube with said loaded capillary tube supported therein on asupporting surface, c. inserting said opposite end of said spacersection into said well of said measurement instrument until said spacersection engages a cooperating surface of said measurement instrument tolimit the movement of the assay tube in the well to a reproducibleposition in which said capillary tube is reproducibly spaced saidprescribed distance from said counting medium, d. taking a measure ofthe radioactivity of said liquid in said capillary tube by said countingmedium while said assay tube is held in said position in said well, saidspacer section being proportioned to hold said loaded capillary tube atsaid prescribed distance from said counting medium, whereby theindication of said instrument is a measure of the radioactivity of saidliQuid.
 2. positioning the capillary tube thus loaded at a prescribeddistance of separation with respect to a radioactivity counting mediumin a radioactivity measurement instrument, which is sensitive to theradiation emanating from said radionuclide and which has a well, saidstep of loading said capillary tube including a. dipping the end of saidcapillary tube into a sample of said liquid thereby to load saidcapillary tube with a precise and reproducible predetermined reducedquantity of said liquid, the step of positioning said capillary tubeincluding: b. placing said capillary tube loaded with said liquid in acompartment section of an assay tube, said compartment section with saidloaded capillary tube contained therein being secured to one end of aspacer section of said assay tube with said loaded capillary tubesupported therein on a supporting surface, c. inserting said oppositeend of said spacer section into said well of said measurement instrumentuntil said spacer section engages a cooperating surface of saidmeasurement instrument to limit the movement of the assay tube in thewell to a reproducible position in which said capillary tube isreproducibly spaced said prescribed distance from said counting medium,d. taking a measure of the radioactivity of said liquid in saidcapillary tube by said counting medium while said assay tube is held insaid position in said well, said spacer section being proportioned tohold said loaded capillary tube at said prescribed distance from saidcounting medium, whereby the indication of said instrument is a measureof the radioactivity of said liQuid.
 2. The method as defined in claim 1further including the step of obtaining a calibration measure of saidinstrument using a calibration sample of a reference radionuclidesubstance in a capillary tube positioned at said prescribed distance ofseparation with respect to said counting medium, said calibration samplebeing proportioned in volume and activity to provide a normalizedmeasure of radioactivity, whereby the radioactivity of said liquid isdeterminable directly by the ratio of the indication of said instrumentfor said liquid with the indication of said instrument for saidreference substance.